The story of drotrecogin alfa – evidence-based or evidence-biased?
To the Editor: In 2003, Taylor et al. 1 posed the question: ‘Should health care money in South Africa be spent on drotrecogin alfa [Xigris]?’ Based on scientific and financial considerations, they concluded that the answer should be ‘no’. In addition to raising questions concerning cost-effectiveness within the South African context, the authors highlighted concerns of the validity of the evidence. Methodological flaws within the PROWESS study2 were noted: the protocol was amended mid-trial, and the study’s beneficial findings were only identified following this amendment, questioning the extent to which they were influenced.
Macias and Levy3 – both employees of Eli Lilly and Company (the manufacturers of Xigris) – refuted the assertions of Taylor et al. by implying that the granting of marketing authorisation by 40 countries defied the ‘lone voice in the wilderness’.
On 25 October 2011, both the US Food and Drug Administration (FDA)4 and European Medicines Agency (EMA)5 announced their intentions to withdraw marketing rights for Xigris in the USA and Europe. This course of action followed the findings of the placebo-controlled PROWESS-SHOCK study: drotrecogin alfa did not elicit a statistically significant reduction in 28-day all-cause mortality, and also failed – in its secondary endpoint – to reduce mortality in patients with severe protein C deficiency.5
Ironically, we echo the concluding remarks of Macias and Levy:3 ‘In evaluating new and novel therapies, health care providers and health care payers should analyse objectively and fairly all available data, be transparent in their decision-making process, and be accountable to patients and their families for their recommendations to accept or reject novel life-saving therapy’. We suggest that this same level of accountability and transparency should be extended to the manufacturing fraternity, ensuring that patients and their families are not offered false hope in the interests of profit generation.
This situation presents valuable learning opportunities for the South African healthcare community: (i) a more critical approach is required towards the analysis of clinical literature presented in support of new chemical entities; especially those that offer marginal benefit, are potentially unsafe, and come at a high cost; (ii) this critical mindset is even more pressing in a resource-poor environment, such as South Africa; and (iii) South Africa can ill afford 8 years of wasteful spending when legitimate concerns regarding safety, efficacy and affordability have been raised in the literature. These warnings need to be heeded earlier to ensure that equitable access is directed towards, rather than away from, interventions of clear clinical benefit.
Medical Advisory Unit
Liberty Health Holdings
Department of Internal Medicine
Division of Clinical Pharmacology
University of Cape Town/Groote Schuur Hospital
1. Taylor B, Burns D, van de Wal BW, et al. Should health care money in South Africa be spent on drotrecogin alfa? S Afr Med J 2003;93(7):500-501.
2. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2011;344:699-709.
3. Macias WL, Levy, H. The value of innovation. S Afr Med J 2003;93(7):502-503.
4. Food and Drug Administration (FDA). Xigris (drotrecogin alfa (activated)): Market Withdrawal – Failure to Show Survival Benefit. Silver Spring, Maryland: FDA, 2011. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm277143.htm (accessed 27 October 2011).
5. European Medicines Agency (EMA). Xigris (drotrecogin alfa (activated)) to be withdrawn due to lack of efficacy. London: EMA, 2011. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/10/news_detail_001373.jsp&mid=WC0b01ac058004d5c1&jsenabled=true# (accessed 27 October 2011).
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